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Endothelial Beta 1-integrins in Cerebral Vascular Barrier Integrity

内皮β1-整合素在脑血管屏障完整性中的作用

基本信息

批准号：
10269018
负责人：
Gregory J Del Zoppo
金额：
$ 53.63万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10269018
关键词：
Acute Adherens Junction Adhesions Adhesives Affect Astrocytes Basal lamina Behavior Biochemical Blood Blood - brain barrier anatomy Blood Vessels Brain Edema Cell Culture Techniques Cell Line Cell Survival Cells Cerebrovascular system Chronic Complex Corpus striatum structure Disease Edema Endothelial Cells Endothelium Event Extravasation F-Actin Feasibility Studies Generations Glues Goals Hour Image Immunoglobulin G In Vitro Injections Injury Integrin Signaling Pathway Integrins Interruption Intervention Ischemia Ischemic Brain Injury Ischemic Stroke Knock-out Liquid substance Magnetic Resonance Imaging Middle Cerebral Artery Occlusion Modeling Molecular Conformation Mus Myosin Light Chain Kinase Myosin Light Chains Outcome PECAM1 gene Pathway interactions Permeability Phosphorylation Prevention Primary Cell Cultures Process Proteins Proteolysis Research Research Project Grants Rho-associated kinase Role Signal Pathway Signal Transduction Stroke Structure Testing Tight Junctions Time Tissues acute stroke adhesion receptor brain endothelial cell cadherin 5 cerebral microvasculature cerebrovascular clinically relevant experimental study improved outcome in vitro Model in vivo in vivo Model inhibitor/antagonist mortality neurovascular nonhuman primate novel preservation prevent response scaffold tissue injury treatment strategy vasogenic edema

项目摘要

Ischemic stroke acutely targets the cerebral microvasculature. Within hours following proximal MCA occlusion, the microvessel endothelial permeability barrier opens causing “vasogenic” edema in the corpus striatum. This process is not fully understood and has no treatment currently. Cerebral microvessel structure and signaling appears central to these acute changes. Interfering with the established adhesion of endothelial cell β1- integrins to the underlying matrix acutely increases T2 but not ADC by 14T MRI within 6 hours, and acutely increases permeability in vitro, alters tight junction (TJ) expression, and alters F-actin conformation, without loss of endothelial cell viability. However, inhibition of myosin light chain (MLC) phosphorylation, within 6 hours in vitro, prevents the permeability increase when established β1-integrin–matrix adhesion is disrupted. Hence, modulating endothelial β1-integrin signaling acutely could preserve the barrier and decrease striatal edema. The hypotheses to be tested in this proposal state that i) interactions of microvessel endothelial cells with their basal lamina matrix proteins through β1-integrin adhesion receptors are a major structural and signaling determinant of blood-brain barrier behavior, ii) focal ischemia disrupts stable β1-integrin–matrix interactions, iii) disruption of these interactions increases microvessel permeability, and iv) this acutely increased permeability and edema can be prevented by inhibiting β1-integrin signaling. The three Specific Aims will demonstrate that: 1) rapid modulation of the MLC and associated β1-integrin signaling can prevent the acute permeability increase caused by interference with β1-integrin–matrix adhesion, 2) experimental ischemia disrupts endothelial cell β1-integrin–matrix adhesion, induces endothelial signaling that increases permeability, and this can be prevented, and 3) focal ischemia, through tissue injury, decreases β1-integrin expression or matrix adhesion, and increases endothelial permeability, which can be prevented. A central role for endothelial cell β1-integrin–matrix adhesion as the determinant of acute “vasogenic” edema in focal ischemia is conceptually novel and testable. With high-quality primary cerebral endothelial cell cultures from wild type and conditional endothelial β1-integrin knockout constructs to define β1-integrin signaling events (Specific Aim 1), in vitro models to quantify the effects of ischemia on endothelial cell β1-integrin signaling (Specific Aim 2), and real- time assessment of acute edema formation in murine stereotaxic injection and MCA occlusion models using real-time 14T MRI to guide acute assessments of permeability and its prevention with signaling inhibitors (Specific Aims 1 and 3), this Project will demonstrate that β1-integrin–matrix adhesion is pivotal to edema prevention. These very feasible studies are a new direction in stroke research that will substantially further our understanding of acute blood-brain barrier behavior under focal ischemia. Understanding β1-integrin signaling mechanisms is also likely to identify novel specific targets to preserve or selectively change endothelial barrier function in other neurovascular disorders, with the aim to improve outcome.

缺血性卒中的急性目标是大脑微血管。近端中动脉闭塞后数小时内，